Collagen is the major structural constituent of mammalian organisms and makes up a large portion of the total protein content of skin and other parts of the animal body. In humans, it is particularly important in the wound healing process and in the process of natural aging. Various skin traumas such as burns, surgery, infection and accident are often characterized by the erratic accumulation of fibrous tissue rich in collagen and having increased proteoglycan content. In addition to the replacement of the normal tissue which has been damaged or destroyed, excessive and disfiguring deposits of new tissue sometimes form during the healing process. The excess collagen deposition has been attributed to a disturbance in the balance between collagen synthesis and collagen degradation.
Keloids are tumors or connective tissue consisting of highly hyperplastic masses which occur in the dermis and adjacent subcutaneous tissue in certain susceptible individuals, most commonly following trauma. The known therapies for keloids have had limited success and they frequently can recur in the site after surgical removal.
Hypertrophic scars are unsightly masses which can result from burns or other injuries to the skin. Such scars are usually permanent and resistant to known methods of therapy.
Depressed scars occur following inflammatory conditions and result in contraction of the skin, leaving a cosmetically unacceptable result. The most common example is the scarring which occurs following inflammatory acne. The condition is common and permanent. The depression occurs as a normal consequence of healing and the scar tissue causing the depression is predominantly composed of collagen.
Post-surgical adhesions sometimes form following surgery or inflammation, wherein the normal healing process may bind structures one to another. An undesirable example is the binding of tendons to tendon sheath. Such adhesions are common complications of surgery and no therapy is available. Collagen is a predominant part of this scarring process.
Acne vulgaris is another common skin disease often causing unsightly facial scars. Some acne patients have been successfully treated for acne scarring using intralesional steroids, liquid nitrogen, dermabrasion and the like. In many cases, however, the lesions do not respond or the treatment results in other complications.
Additional disfiguring conditions such as wrinkling, cellulite formation and neoplastic fibrosis also appear to result from excessive collagen deposition which produces unwanted binding and distortion of normal tissue architecture.
Enzymes are proteinaceous substances which act as catalysts for biological reactions; in some cases hydrolysis reactions and in others oxidation-reduction processes. Some enzymes have broad activity and others, such as collagenase (Clostridiopeptidase A) produced from the bacterium Clostridium hystolyticum, have very specific activity. Highly purified collagenase has been prepared and been found uniquely capable of cleaving bonds in the collagen structure permitting other enzymes to act on the resulting molecular fragments.
The use of collagenase in medical practice is well known but has heretofore been limited to topical application for debridement of dermal ulcers and burns and, recently, for the treatment of prolapsed intervertebral discs. Purified collagenase has been demonstrated to be relatively safe even in large doses (thousands of units) in animals and in contact with human blood vessels, nerves and bones.
Hyaluronidase is a soluble enzyme product prepared from mammalian testes. It has been previously used in human medicine to increase the effect of local anesthetics and to permit wider infiltration of subcutaneously administered fluids.
Elastase is an enzyme obtained from dried pancreas or from leukocytic origins and which can be electrophoretically or otherwise purified and standardized by assay. The most characteristic trait of elastases is its capacity to break down elastin, the specific protein of elastic fibers.
Papain is a proteolytic enzyme or mixture of enzymes prepared from papaya fruit which hydrolyzes polypeptides, amides and esters, yielding peptides of lower molecular weight. It is one of the most thermostable enzymes and has commercial uses in the food industry.
Plasminogen activator is a neutral proteinase secreted by mononuclear phagocytes, prominent cells in the host defense characteristic of chronic inflammatory responses. Plasminogen activator is believed to mediate extracellular protein degradation by macrophages in the presence of plasmonogen.
Plasmin is a proteolytic enzyme, derived from the activation of human plasminogen by highly purified streptokinase, which dissolves fibrin. Plasmin has fibrinolytic properties and also contains a plasminogen activator. It has been used for the treatment of thrombotic disorders, as an adjunct to anti-coagulant therapy and for the debridement of wounds in conjunction with deoxyribonuclease.
Lysosomal hydrolase is an enzyme derived from body cells, e.g. the liver, which catalyzes the removal of water from a substrate. It has been hypothesized that the degradation of connective tissue involves two distinct steps--an initial extracellular cleavage of insoluble proteins mediated by neutral proteinases, followed by endocytosis and completion of digestion within lysosomes.
Mast cell protease is a neutral proteolytic enzyme extracted from the media or cultured metastatic tumor cells and highly purified by sequential ammonium sulfate fractionization, column chromatography and molecular sieve chromatography. It has been shown to be especially effective in cleaving type IV collagen.